The decarboxylation of ornithine to putrescine, a reaction catalysed by the enzyme ornithine decarboxylase (ODC), is the first step in the biosynthesis of the polyamines, spermidine and spermine. Spermidine is formed by the spermidine synthase catalysed transfer of an activated aminopropyl moiety from S-adenosyl S-methyl homocysteamine to putrescine, while spermine is formed by the spermine synthase catalysed transfer of a second aminopropyl group to spermidine. S-adenosyl S-methyl homocysteamine is formed by the decarboxylation of S-adenosylmethionine (SAM), a reaction catalysed by the enzyme S-adenosylmethionine decarboxylase (SAM-DC).
The polyamines, spermidine and spermine, which are found in all animal tissues and certain microorganisms, such as protozoa, are known to play an important role in cell growth and proliferation. The induction of cell growth and proliferation is associated with both a marked increase in ODC activity and an increase in the levels of putresine and the polyamines. Although the exact mechanism of the role of the polyamines in cell growth and proliferation is not known, it appears that the polyamines may facilitate macromolecular processes such as DNA, RNA, or protein synthesis. Polyamine levels are known to be high in embryonic tissue; in the testes, ventral prostate, and thymus; in neoplastic tissue; in psoriatic skin lesions; and in other cells undergoing rapid replication.
Since the polyamines are formed enzymatically, it is seen that inhibition of aminopropyltransferase (i.e. spermidine synthase and/or spermine synthase), can provide a method for regulating the cellular levels of the polyamines. The administration of an aminopropyltransferase inhibitor, thus, can provide a means for controlling the growth of protozoa, wherein the polyamines are important for cell replication, for treating certain disorders associated with rapid cell proliferation (for example, in neoplasms, epidermal hyperplasia, e.g. psoriasis, and prostatic hypertrophy) and for interrupting embrypgenic development (contragestational activity).
It has been proposed in a paper by Coward (Drug Action and Design: Mechanism-Based Enzyme Inhibitors; Elsevier North Holland, 1979 at pages 13 to 26) that aminopropyltransferase would be inhibited by methylsulfonium adducts of the following general Formula A: ##STR2## wherein:
R represents hydrogen or 3-aminopropyl. It is reported in that paper (at page 17) that the adducts had not been prepared but that it was hoped that deblocking and methylation of a totally blocked thioether precursor would yield the compound of Formula A in which R represents hydrogen. In a subsequent paper by Coward and fellow workers (Tang et al, Biochem. Biophys. Research Communications 96, 1371-1377 (1980)) received and published after the priority date of the present application there is reported the inhibition of aminopropyltransferase by an adenosine-5'-thioether of the following Formula B and a corresponding methyl sulfonium salt of the following Formula C: ##STR3##
It has been reported (Pankaskie and Abdel-Monem, J. Med. Chem. 23, 121-127 (1980)) that a methyl-sulfonium adduct of the following Formula D and the corresponding N-methylamino compound of the following Formula E are inhibitors of SAM-DC: ##STR4##